Hepatocellular carcinoma (HCC) is a malignant tumor of liver that causes approximately half a million deaths each year, of which over half of the cases are diagnosed in China. Because of its asymptomatic nature, HCC is usually diagnosed at late and advanced stages, for which there are no effective therapies. Thus, biomarkers for early detection and molecular targets for treating HCC are urgently needed. With the advent of high-throughput omics technologies, we have begun to mine the genomics and proteomics information of HCC, and most importantly, these data can be integrated with clinical annotations of the patients. Such new horizons of integrated profiling informatics have allowed us to search for and better identify clinically useful biomarkers and therapeutic targets for cancers including HCC. Capitalizing the large clinical samples cohort (over 100 pairs of tumor and matched adjacent nontumor tissues of HCC), we herein discuss the use of proteomics approach to identify biomarkers that are potentially useful for (1) discrimination of tumorous from nonmalignant tissues, (2) detection of small-sized and early stage of HCC, and (3) prediction of early disease relapse after hepatectomy.